neuroscience

Deciphering Herpes Hybridization

Herpesviruses reproduce in an unusual way. Normally, DNA viruses replicate their genes by copying each strand of the double-stranded DNA. But researchers have suspected that herpesvirus uses recombination — exchanging one version of a gene with another related version — to replicate. Now, UConn Health researchers from Sandra Weller’s lab have found another clue: a specific viral protein that seems essential to the new DNA’s ability to assimilate into the strand. This protein may provide a target for new herpes drugs. Blocking the protein responsible for the insertion event prevents the virus from copying its own DNA. If it can’t copy its DNA, it can’t reproduce, and so the herpesvirus can’t be infectious or reactivate after going dormant.

Electron micrograph of HHV-6, human herpesvirus-6

‘Stealth Condition’ Riskier Than Previously Thought

The Western world’s most common genetic disorder is a “stealth condition” that causes far more death and disability than previously thought. Hemochromatosis, which causes people to absorb too much iron from their food, quadruples the risk of liver disease, doubles the risk of arthritis and frailty in old age, and causes a higher risk of diabetes and chronic pain, report researchers at UConn Health and the University of Exeter. It’s thought that the extra iron absorption was advantageous for northern European women eating poor diets, but is harmful in today’s iron-rich food supply. Although more than 1 million Americans have hereditary hemochromatosis, few doctors are taught to look for the condition in the early stages of joint pain and tiredness, when it can be easily treated.

Moving the Motivation Meter

Two novel drugs kick-start motivation in rats suffering from apathy and a lack of oomph, UConn researchers led by behavioral neuroscientist John Salamone reported at the 2018 Society for Neuroscience conference in San Diego. Both of the experimental drugs cause a buildup of dopamine in the synapses between brain cells. Stimulants like amphetamines and cocaine do the same thing, but in a much more extreme way. The researchers are now testing other, chemically related drugs to see which are most effective and have the least potential for abuse. Lack of motivation is a common symptom of depression that’s harder to treat than other symptoms; the findings could point toward potential treatments.

Targeting Tricky Tuberculosis

Tuberculosis is a sneaky disease. The bacteria that cause it allow themselves to be eaten by the immune cells sent to destroy them. But instead of dying, mycobacterium tuberculosis sets up housekeeping and multiplies before busting out to infect more cells. Antibiotics can’t get inside the immune cells, so the only time the mycobacterium are vulnerable are when they’ve just broken out and are cruising for a new cell to infect. But now, UConn chemist Alfredo Angeles-Boza and his colleagues have found certain antibiotic proteins from fish can get at the mycobacterium where they hide, and report their results in ACS Infectious Diseases.

Certain blood vessels in the brainstem constrict when blood vessels elsewhere in the body would dilate. And that contrary behavior is what keeps us breathing, according to a new paper by UConn researchers published in the journal eLife.

Neuroscientists studying the brainstem have historically focused on neurons, which are brain cells that send signals to one another and all over the body. Recently, neuroscientists have come to understand that astrocytes, cells once thought to simply provide structure to the brain, also release signaling molecules, which regulate neuron function. But until now, no one even considered the possibility that blood vessels may be similarly specialized.

For more than a century, doctors and scientists have known that blood vessels dilate when cellular waste products like carbon dioxide build up. Widening the vessels allows fresh blood to flush through, carrying in oxygen and washing away the acidic carbon dioxide. This has been shown to be true throughout the body, and is standard dogma in undergraduate physiology classes.

Neuroscientists have come to understand that astrocytes release signaling molecules that regulate neuron function. Until now, no one even considered the possibility that blood vessels may be similarly specialized.

UConn physiologist Dan Mulkey was teaching exactly that to undergraduates one day when he realized that it couldn’t possibly be true in the part of the brainstem he studies. The retrotrapezoid nucleus (RTN), a small region in the brainstem, controls breathing. Mulkey has shown in the past that RTN neurons respond to rising levels of carbon dioxide in brain tissue by stimulating the lungs to breathe. But if the blood vessels in the RTN dilated in response to rising carbon dioxide the same way blood vessels do everywhere else, it would wash out that all-important signal, preventing cells in the RTN from doing their job of driving us to breathe.

Mulkey’s team, primarily comprising UConn undergraduates, studied thin slices of brainstem and found that RTN blood vessels constricted when carbon dioxide levels rose. But blood vessels from slices of cortex (the wrinkled top part of the brain) dilated in response to high carbon dioxide, just like the rest of the body.

Mulkey guessed that astrocytes had something to do with the change in blood vessel behavior, and his hypothesis was proved right in the lab. The astrocytes in the RTN were behaving differently than astrocytes anywhere else in the body. When these brainstem astrocytes detected high levels of carbon dioxide, they released adenosine triphosphate signaling to the neurons and blood vessels that they should constrict.

“This is a big change in how we think about breathing,” Mulkey says.

UConn physiologist Dan Mulkey discovered that astrocytes, cells that tell neurons how to behave, signal blood vessels in part of the brainstem to constrict in reaction to carbon dioxide rather than dilate, like they do elsewhere in the body. This contrary behavior enables us to breathe.

Melanoma’s Signature

Dangerous melanomas likely to metastasize have a distinctive molecular signature, UConn Health researchers reported in the February issue of Laboratory Investigation. Melanomas are traditionally rated on their thickness; very thin cancers can be surgically excised and require no further treatment, while thick ones are deemed invasive and require additional therapies. But melanomas of intermediate thickness are harder to judge. The researchers measured micro-RNAs produced by melanoma cells and compared them with the micro-RNAs in healthy skin. Micro-RNAs regulate protein expression in cells. The team found that melanomas with the worst outcomes produced lots of micro-RNA21 compared to melanomas of similar thickness with better outcomes. In the future this molecular signature could help dermatologists decide how aggressively to treat borderline melanomas.

Chili Pepper and Marijuana Calm the Gut

The medical benefits of marijuana are much debated, but what about those of chili peppers? It turns out that when eaten, both interact with the same receptor in our stomachs, according to UConn Health research published in the April 24 issue of Proceedings of the National Academy of Sciences. The scientists found feeding mice chili peppers meant less gut inflammation and cured those with Type 1 diabetes. Why? The chemical capsaicin in the peppers bonds to a receptor found in cells throughout the gastrointestinal tract, causing the cells to make anandamide — a compound chemically akin to the cannabinoids in marijuana. The research could lead to new therapies for diabetes and colitis and opens up intriguing questions about the relationship between the immune system, the gut, and the brain.

Isolating Their Target

Brain cells of individuals with Angelman syndrome fail to mature, disrupting the ability of the cells to form proper synaptic connections and causing a cascade of other developmental deficits that result in the rare neurogenetic disorder, according to UConn Health research. Neuroscientist Eric Levine’s team used stem cells derived from Angelman patients to identify the disorder’s underlying neuronal defects, an important step in the ongoing search for potential treatments and a possible cure. Previously, scientists had relied primarily on mouse models that mimic the disorder. The findings were published in the April 24 issue of Nature Communications. While Levine’s team investigates the physiology behind the disorder, UConn developmental geneticist Stormy Chamberlain’s team researches the genetic mechanisms that cause Angelman.

The Cornea’s Blindness Defense

The formation of tumors in the eye can cause blindness. But for some reason our corneas have a natural ability to prevent that from happening. Led by Royce Mohan, UConn Health neuroscientists believe they have found the reason, findings that will be detailed in September’s Journal of Neuroscience Research. They link the tumor resistance to a pair of catalytic enzymes called extracellular signal-regulated kinases 1 and 2. When ERK1/2 are overactivated in a specific type of cell, the “anti-cancer privilege of the cornea’s supportive tissue can be overcome,” says Mohan. That happens in the rare disease neurofibromatosis-1. “These findings may inform research toward developing better strategies for the prevention of corneal neurofibromas,” says Dr. George McKie, cornea program director at the National Eye Institute, which funded the study.